Kristen E. D'Anci, PhD; Stacey Uhl, MS; Gina Giradi, MS; Constance Martin, BA
Financial Support: By the U.S. Department of Veterans Affairs Veterans Health Administration.
Disclosures: Dr. D'Anci reports grants from the U.S. Department of Veterans Affairs during the conduct of the study. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M19-0869.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Catharine B. Stack, PhD, MS, Deputy Editor, Statistics, reports that she has stock holdings in Pfizer, Johnson & Johnson, and Colgate-Palmolive. Christina C. Wee, MD, MPH, Deputy Editor, reports employment with Beth Israel Deaconess Medical Center. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Yu-Xiao Yang, MD, MSCE, Deputy Editor, reports that he has no financial relationships or interest to disclose.
Reproducible Research Statement: Study protocol: Available at www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=104978. Statistical code: Not applicable. Data set: See the Supplement.
Corresponding Author: Kristen E. D'Anci, PhD, Senior Associate Director, Center for Clinical Evidence and Guidelines, ECRI Institute, 5200 Butler Pike, Plymouth Meeting, PA 19462-1298; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. D'Anci, Ms. Uhl, Ms. Giradi, and Ms. Martin: Center for Clinical Evidence and Guidelines, ECRI Institute, 5200 Butler Pike, Plymouth Meeting, PA 19462-1298.
Author Contributions: Conception and design: K.E. D'Anci, S. Uhl.
Analysis and interpretation of the data: K.E. D'Anci, S. Uhl.
Drafting of the article: K.E. D'Anci, S. Uhl, G. Giradi, C. Martin.
Critical revision of the article for important intellectual content: K.E. D'Anci.
Final approval of the article: K.E. D'Anci, S. Uhl, G. Giradi, C. Martin.
Statistical expertise: K.E. D'Anci.
Collection and assembly of data: K.E. D'Anci, S. Uhl, G. Giradi, C. Martin.
Suicide is a growing public health problem, with the national rate in the United States increasing by 30% from 2000 to 2016.
To assess the benefits and harms of nonpharmacologic and pharmacologic interventions to prevent suicide and reduce suicide behaviors in at-risk adults.
MEDLINE, EMBASE, PsycINFO, and other databases from November 2011 through May 2018.
Systematic reviews (SRs) and randomized controlled trials (RCTs) that assessed nonpharmacologic or pharmacologic therapies for adults at risk for suicide.
One investigator abstracted data and assessed study quality, and a second investigator checked abstractions and assessments for accuracy.
Eight SRs and 15 RCTs were included. The evidence for psychological interventions suggests that cognitive behavioral therapy (CBT) reduces suicide attempts, suicidal ideation, and hopelessness compared with treatment as usual (TAU). Limited evidence suggests that dialectical behavior therapy (DBT) reduces suicidal ideation compared with wait-list control or crisis planning. The evidence for pharmacologic treatments suggests that ketamine reduces suicidal ideation with minimal adverse events compared with placebo or midazolam. Lithium reduces rates of suicide among patients with unipolar or bipolar mood disorders compared with placebo. However, no differences were observed between lithium and other medications in reducing suicide.
Qualitative synthesis of new evidence with existing meta-analyses, methodological shortcomings of studies, heterogeneity of nonpharmacologic interventions, and limited evidence for pharmacologic treatments and harms.
Both CBT and DBT showed modest benefit in reducing suicidal ideation compared with TAU or wait-list control, and CBT also reduced suicide attempts compared with TAU. Ketamine and lithium reduced the rate of suicide compared with placebo, but there was limited information on harms. Limited data are available to support the efficacy of other nonpharmacologic or pharmacologic interventions.
U.S. Department of Veterans Affairs Veterans Health Administration. (PROSPERO: CRD42018104978)
Appendix Table 1. Literature Search Strategy: EMBASE Syntax
Appendix Table 2. Literature Search Strategy: PsycINFO Syntax
Appendix Table 3. Literature Search Strategy: PILOTS Database Syntax
Appendix Table 4. Study Quality Checklist for RCTs, Based on USPSTF Criteria
Evidence search and selection.
KQ = key question; SR = systematic review.
* Not relevant to topic, not published in English, or published before inclusion date.
† Not clinical trial or SR, did not address KQ, did not report on outcome of interest, or outside publication cutoff dates.
Table 1. Nonpharmacologic Interventions for Suicide Prevention*
Table 2. Evidence for Other Nonpharmacologic Interventions*
Table 3. Pharmacologic Interventions for Suicide Prevention*
Deanna L. Kelly, David A. Gorelick, Heidi J. Wehring, Gopal Vyas, Robert W. Buchanan
University of Maryland School of Medicine
October 4, 2019
Conflict of Interest:
Deanna Kelly is a consultant for Alkermes and HLS Therapeutics.
Robert Buchanan is on the Advisory Board for GW Pharma Limited and Minerva. He also serves on the DSMB for Roche.
Clozapine Use in the Treatment of Suicidality in People with Schizophrneia
To the Editor: The systematic review by D’Anci and colleagues (1) is a welcome addition to the literature on the prevention and treatment of suicidality, a major public health crisis in the United States. However, their criterion of including only double-blind, randomized clinical trials leads them to omit mention of clozapine, one of the few medications with proven efficacy for the treatment of suicidality. Clozapine, an antipsychotic medication, was approved by the Food and Drug Administration (FDA) for the indication of reducing the risk of recurrent suicidal behavior in people with schizophrenia or schizoaffective disorder. This approval was based on the results of a large (980 participants), long-term (18 months), multi-site, randomized, single-blind clinical trial comparing clozapine with olanzapine in patients with schizophrenia or schizoaffective disorder at high risk for suicidality (2). While the treating clinicians were not blinded, the outcome raters were blind to treatment group. The clozapine group had significantly less suicidality: hazard ratio 0.76 (95% CI 0.58-0.97) and the calculated Number Needed to Treat (NNT) to reduce suicidality was 13. To our knowledge, clozapine is the only medication that is FDA approved for the indication of suicidality, although there is certainly substantial clinical evidence supporting the efficacy of lithium, as described by D’Arcy and colleagues (1). In short, we believe that the decision by D’Anci and colleagues to exclude single-blind randomized clinical trials from their systematic review ignored the difficulty of conducting double-blind clinical trials in seriously ill patient populations (3) and resulted in omission of an FDA-approved medication that is included in many clinical practice guidelines for treatment of suicidality (4,5). We recommend that clozapine be considered for use in the treatment of suicidality in people with schizophrenia or schizoaffective disorder.Deanna L. Kelly, PharmD, BCPPProfessorUniversity of Maryland School of Medicinedlkelly@som.umaryland.eduDavid A. Gorelick, MD, PhD, DLFAPAProfessorUniversity of Maryland School of Medicinedgorelick@som.umaryland.eduHeidi J. Wehring, PharmD, BCPPAssistant ProfessorUniversity of Maryland School of Medicinehwehring@som.umaryland.eduGopal Vyas, DOClinical Assistant ProfessorUniversity of Maryland School of Medicinegopalvyas@som.umaryland.eduRobert W. Buchanan, MD University of Maryland School of Medicinerwbuchanan@som.umaryland.eduReferences1. D'Anci KE, Uhl S, Giradi G, et al. Treatments for the Prevention and Management of Suicide: A Systematic Review. Ann Intern Med. Sep 3 2019;171(5):334-342.2. Meltzer HY, Alphs L, Green AI, et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Archives of general psychiatry. Jan 2003;60(1):82-91.3. Conducting Research with Participants at Elevated Risk for Suicide: Considerations for Researchers. Available at: https://www.nimh.nih.gov/funding/clinical-research/conducting-research-with-participants-at-elevated-risk-for-suicide-considerations-for-researchers.shtml. Accessed 10/2/19.4. Buchanan RW, Kreyenbuhl J, Kelly DL, et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophrenia bulletin. Jan 2010;36(1):71-93.5. Sall J, Brenner L, Millikan Bell AM, et al. Assessment and Management of Patients at Risk for Suicide: Synopsis of the 2019 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guidelines. Ann Intern Med. Sep 3 2019;171(5):343-353.
Kristen E. D’Anci, Stacey Uhl
November 5, 2019
Thank you for your comments regarding the use of clozapine in the treatment of suicidality in people with schizophrenia or schizoaffective disorder. Clozapine is recognized and recommended as a treatment to reduce death by suicide among adults with schizophrenia or schizoaffective disorder in the 2019 VA/DoD clinical practice guideline on the assessment and management of patients at risk the risk suicide (1). This recommendation was carried forward from the previous VA/DoD guideline on the management of suicide published in 2013, and is based largely on the Meltzer study that is cited in your comments (2,3). As it was included in the previous versions of the guideline, it was not discussed in the newly updated systematic review.The systematic review published by D’Anci et al. (4) and the accompanying 2019 VA/DoD guideline (1) serve to update the evidence and recommendations in the 2013 guideline. As part of our methodological approach, the search dates for the current systematic review encompassed the end date of the literature search in the previous guideline (18 November 2011), and extended the searches through May 2018. The Meltzer study (3) that is cited in the comments was outside the search dates of the current systematic review and would not have been retrieved in the search results. The newer search results did not identify any recent studies addressing the use of clozapine in the treatment of suicide that met inclusion criteria for the systematic review. Thus, there was no new evidence on clozapine to discuss in the updated systematic review or to add to the previous recommendation on the use of clozapine as a treatment for suicide risk among adults. Given space considerations, it is generally not possible to cover all topics that do not yield new evidence, particularly if a recommendation is already underpinned by previous evidence. However, we welcome the opportunity to clarify the use of previously identified literature in new versions of an established VA/DoD clinical practice guideline.Kristen E. D’Anci, Ph.D.Senior Associate DirectorECRI Institute Center for Clinical Evidence and Guidelineskdanci@ecri.orgStacey Uhl, M.S.Associate DirectorECRI Institute Center for Clinical Evidence and Guidelinessuhl@ecri.orgECRI Institute5200 Butler PikePlymouth Meeting, PA 19462-1298, USA1. Sall J, Brenner L, Millikan Bell AM, et al. Assessment and Management of Patients at Risk for Suicide: Synopsis of the 2019 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guidelines. Ann Intern Med. Sep 3 2019;171(5):343-353.2. U.S. Department of Veterans Affairs. VA/DoD Clinical Practice Guidelines. Washington, DC: U.S. Department of Veterans Affairs, Veterans Health Administration. Accessed at www.healthquality.va.gov/index.asp on 5 November 2019.3. Meltzer HY, Alphs L, Green AI, et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. Jan 2003;60(1):82-91. 4. D'Anci KE, Uhl S, Giradi G, et al. Treatments for the Prevention and Management of Suicide: A Systematic Review. Ann Intern Med. Sep 3 2019;171(5):334-342.
D'Anci KE, Uhl S, Giradi G, et al. Treatments for the Prevention and Management of Suicide: A Systematic Review. Ann Intern Med. 2019;171:334–342. [Epub ahead of print 27 August 2019]. doi: https://doi.org/10.7326/M19-0869
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Published: Ann Intern Med. 2019;171(5):334-342.
Published at www.annals.org on 27 August 2019
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